Many blood tests must be performed on plasma without cellular matter present. In the standard laboratory protocol, pure plasma is obtained through centrifugation. In order to produce a miniaturized blood sensor, a method to separate plasma other than centrifugation is needed.
Chemical analysis of biological samples is constrained by sample size. Withdrawing a few milliliters of blood from an adult may have little effect, but repeating this procedure every hour or even withdrawing this amount once from an infant can significantly alter the health of the subject. For these reasons, a miniaturized blood analysis system would be useful. Furthermore, while many sophisticated tests that have great importance for critical care can be performed in major hospital laboratories, a substantial impact could be made on the practice of emergency medicine if some key tests could be performed on the patient at the site of injury.
Microfabricated fluid filters exist in the literature; however, these lack the advantages of the microfilter of the present invention.
Kittisland, G., and Stemme, G. (1990), "A Sub-micron Particle Filter in Silicon," Sensors and Actuators, A21-A23:904-907; and Stemme, G. and Kittisland, G. (1988), "New fluid filter structure in silicon fabricated using a self-aligning technique," Appl. Phys. Lett. 53:1566-1568, describe microfilters fabricated using a silicon wafer and capable of filtering out particles down to 50 nm. This filter design cannot be etched into the surface of a silicon wafer. Further, although these filters seem to perform well for gases, surface tension causes problems when filtering liquids. Gravesen, P., et al. (1993), "Microfluidics--a review," J. Micromech. Microeng. 3:168-182.
Wilding, P., et al. (1994), "Manipulation and Flow of Biological Fluids in Straight Channels Micromachined in Silicon," Clin. Chem. 40:43-47 disclose microfilters useful for separating blood cells from plasma etched into silicon wafers using a photolithographic process. These filter designs do not allow tangential or crossflow of the feed material past the barrier, which may be a narrower channel or barrier posts, to clear the barrier of particles. Further, in all cases, pressure must be applied to the system to obtain analyzable quantities of plasma. Because the minimum dimension of these filters is determined by a photolithographic process, they have a limit of about 1 micron. The photolithographic process is more sensitive to defects and requires tighter constraints on manufacturing than a process that relies on etching time to define the size of the channels as is used herein.
Wilding, P., et al. U.S. Pat. No. 5,304,487 issued Apr. 19, 1994 discloses mesoscale analytical devices for fluid handling comprising flow channels and fluid handling regions micromachined into silicon wafers. Again, no microfilters having tangential flow capabilities to aid in keeping the barrier free of particles are disclosed.
Raehse, W., et al. U.S. Pat. No. 4,751,003 issued Jun. 14, 1988 discloses a microfilter using a crossflow principle having polysulfone tubes with micropore diameters of 0.3 to 0.5 microns disposed in a cylindrical configuration. Ehrfeld, W. et al. U.S. Pat. No. 4,797,211 issued Jan. 31, 1989 discloses a crossflow microfilter comprising a microporous membrane having slit-shaped cross-sections. Solomon, H., et al. U.S. Pat. No. 4,212,742 issued Jul. 15, 1980 discloses a filtration apparatus for separating blood cells from liquids utilizing crossflow principles comprising multiple layers and membrane filters.
Ehrsam, C. et al. U.S. Pat. No. 4,801,379 issued Jan. 10, 1989 discloses a microfilter made of a foil having pores set into protuberances on the foil to aid in prevention of clogging. Hillman, R. U.S. Pat. No. 4,753,776 issued Jun. 28, 1988 discloses a microfilter useful for separating plasma from red blood cells comprising glass fibers using capillary action to promote flow.
Shoji, S. and Esashi, M. (1994), "Microflow devices and systems," J. Micromechanics and Microengineering 4:157-171, provide a general review of microvalves, micropumps, microflow sensors and integrated flow systems.
None of the foregoing references disclose or suggest the microfilter design disclosed herein which provides for tangential flow, ease and control of manufacturing, and minimization of surface tension problems.
All patents and publications referenced herein are incorporated by reference herein in their entirety.